Effect Of Nmda Receptor Antagonists On The Expression Of Cpp Produced By Drugs Of Abuse

To investigate the putative effects of NMDA receptor antagonists on the expression of drug-induced CPP, one can give a single injection of NMDA antagonist before the final measurement (posttest). Studying the inhibitory effects on the expression of conditioned reward produced by drugs (rather than on the acquisition of drug-environment associations) approaches the therapeutic standpoint much closer. It may be hypothesized that the treatment able to diminish the secondarily rewarding effects of drugs would likely diminish the incentive properties of drug-related cues and environments. It has been well documented that individuals recovering from drug and alcohol addiction remain highly susceptible to the environmental stimuli associated with previous exposure to drugs (37,38). This abnormal reactivity of the neural systems, altered by repetitive pairing of drug effects and specific environments or situations, represents a form of learning and is postulated to underlie the vulnerability to relapse for a long time after the termination of drug use (39). The main feature of the ideal pharmacological treatment for addictions would thus be the protective effect against the conditioned and other factors that are known to increase risk of the relapse.

The inhibitory effects of NMDA receptor antagonists on the expression of morphine-induced CPP have been shown for kynurenic acid (17), ACPC (26), NPC 17742 (24), and MK-801 (20). Data from this laboratory showed similar inhibitory effects of memantine, MRZ 2/570, MRZ 2/579, and L-701,324 on the expression of morphine-induced CPP (21,27). Memantine appeared to act selectively, because given at the doses that inhibited morphine reward, it did not affect the expression of food-induced CPP.

The effects of intracerebral injections of NMDA receptor antagonist on the expression of morphine-induced CPP were investigated by Popik and Kolasiewicz (24). These data provide some insight into the mechanism by which NMDA receptor antagonists inhibit the expression of conditioned reward produced by drugs of abuse. Several lines of evidence indicate the essential involvement of mesolimbic areas as the major neural substrate of the reward produced by drugs of abuse (40). Among other elements, this system consists of dopaminergic cells in the ventral tegmental area and their projections to the regions such as nucleus accumbens. Opiates potently activate dopaminergic mesolimbic neurons through the inhibition of inhibitory GABAergic interneurons (41) that subsequently increases dopaminergic transmission to the nucleus accumbens (42). Such activation is thought to be associated with a reward or the feeling of euphoria that—through a complicated and not completely understood mechanism(s)—may ultimately lead to compulsive drug-seeking and drug-taking.

NPC 17742 has been found to significantly reduce the expression of morphine-induced CPP when injected into the nucleus accumbens and ventral tegmental area (24). Although the effects of the higher dose of intra-accumbens NPC 17742 produced behavioral stimulation, intrategmental injection did not change it. These findings demonstrate that stimulation of NMDA receptors in the nucleus accumbens and ventral tegmental area are necessary for the expression of morphine-induced CPP and suggest that alteration of locomotor activity produced by NMDA receptor antagonists are not essential for these agents to be effective attenuating reinforcing effects of morphine.

With regard to other drugs of abuse, the data, again, are less abundant. The expression of cocaine-induced CPP was unaffected by MK-801 (29) or L-701,324 (22). Gruca and Papp (26) reported that ACPC blocked the expression of CPP induced by nicotine and diazepam, but not that induced by cocaine, amphetamine, and nomifensine.

5. THE EFFECT OF NMDA RECEPTOR ANTAGONISTS ON THE MAINTENANCE OF CPP PRODUCED BY DRUGS OF ABUSE

The inhibitory effects of NMDA receptor antagonists on the acquisition and expression of conditioned reward produced by drugs of abuse discussed in the preceding sections, if applied within clinical settings, would perhaps facilitate the process of detoxification, although they may not lead to the elimination of drug addiction per se. Therefore, it may be hypothesized that the ideal "antiaddictive" medication should be able to inhibit the process of ongoing addiction/dependence (i.e., to inhibit and/or eliminate the maintenance of the addictive state). In fact, CPP produced by heroin (43) and morphine (21) lasts for several days or even weeks, indicating that the state of association between the unconditioned drug stimulus and conditioned environmental cues is maintained for a substantial time. Similar observations have been made in human addicts and show that a presentation of a stimulus associated with heroin taking may evoke heroin craving long after detoxification (39).

It was hypothesized (21) that the treatment with a NMDA receptor antagonist should inhibit the maintenance of conditioned morphine reward (i.e., the abnormal reactivity of the neural systems altered by repetitive pairing of drug effects and specific environments), as it inhibits the maintenance of morphine dependence (44). Thus, groups of rats were conditioned to morphine-rewarding effects, and at the end of conditioning, their preference to the morphine-associated environment has been found, as expected. During the subsequent 3 d (i.e., after conditioning), these subjects received twice a day injections of the glycine/NMDA antagonist L-701,324 or MRZ 2/570, or the channel blocker MRZ 2/579. The preference to the morphine-associated environment investigated in drug-free rats on the next day indicated that the treatment with NMDA receptor antagonists did not influence the maintenance of the conditioned response to morphine (21). These data suggest that NMDA receptor antagonists may not influence the maintenance of CPP induced by morphine.

6. EFFECTS OF NMDA RECEPTOR ANTAGONISTS IN OTHER MODELS OF CONDITIONED REWARD

The above- summarized findings are supported by the still limited evidence generated using other types of drug conditioning paradigm such as conditioned facilitation of intracranial self-stimulation (45) and conditioned reinstatement of intravenous cocaine self-administration (46). Interestingly, NMDA receptor blockade may effectively counteract the ability of abused drugs (amphetamine) to potentiate the responding for conditioned reward (47) (see, however, ref. 48 for opposite effect with memantine used at a fairly high dose).

In conclusion, antagonists of NMDA receptor appear to inhibit a conditioned reward produced by drugs of abuse (particularly opiates and psychostimulants). Preliminary clinical findings described in other chapters of this volume strongly suggest that the same effects can be observed in humans. It could be expected that a medication that has NMDA receptor antagonist properties might be a useful pharmacotherapy for disorders related to abuse of a variety of substances. The most promising candidates for such development in the near future include low-affinity NMDA receptor channel blockers like memantine, dextromethorphan, and MRZ 2/579 (Nerimexane®). Others include glycine-site antagonists and, perhaps, other noncompetitive antagonists.

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